ORCID

https://orcid.org/0000-0003-3562-1133

Date of Award

2022

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Abu Serajuddin

Second Advisor

Nitesh Kunda

Third Advisor

Tanaji Talele

Abstract

Fused deposition modeling (FDM) 3D printing has emerged as the most suitable 3D printing technology to develop personalized and on-demand medications. However, the technology faces challenges, such as slow and incomplete drug release, lack of drug-polymer miscibility for poorly water-soluble drugs, limited availability of polymers with acceptable physicochemical properties, and printability. In the present investigation, these issues were addressed using a novel physicochemical principle called acid-base supersolubilization, where a weakly basic drug, haloperidol, interacted with non-salt forming weak acids, glutaric acid or malic acid, and was mixed with polymers by HME to prepare filaments for 3D printing. Haloperidol, having pH-dependent solubility, was used as the model drug, and glutaric acid and malic acid were selected as supersolubilizing agents. The formulations containing either haloperidol-glutaric acid 1:2 molar mixture or haloperidol-malic acid mixture (1:1 and 1:2 molar ratios) along with Kollidon® VA64 or its mixture with Affinisol HPMC 15cP as polymeric carriers. They were extruded into filaments and printed into tablets. The aqueous solubility of haloperidol increased from <2.5 µg/mL at pH>8 to over 300 mg/ml in the presence of weak acid. Moreover solid dispersions of ternary drug-polymer-acid mixtures were stable with as high as 50% drug load due to the formation of a co-amorphous system of drug-acid. The formation of the co-amorphous system decreased extrusion and printing temperatures as low as 115 °C and 100 °C, respectively, and the filament printability was maintained up to 30% drug load. Moreover, complete and pH-independent drug release was achieved within 60 minutes. The ductility and toughness of drug-loaded filaments were limitations of FDM 3D printing of high drug-loaded extrudates, and to overcome them, injection molding was tried as an alternative tableting approach. Haloperidol-Kollidon® VA64-acid mixtures could be successfully molded into tablets at as high as 40% drug load. Although somewhat slower than the 3D-printed tablets, complete and pH-independent drug release was obtained. The application of the ABS principle in the present investigation to increase drug release, enhance drug-polymer miscibility, improve the printability of filaments, and reduce processing temperature may represent a breakthrough in the development of FDM 3D-printed tablets.

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